The long-term goal of this project is to develop respiratory syncytial virus (RSV) vaccine candidates for elderly populations. RSV is a significant pathogen of the elderly rivaling influenza in its impact on the health of this population. Currently it is estimated that RSV infections in the elderly result in 11,000 to 17,000 deaths per year in the US and ten times that number of RSV associated hospitalizations. The worldwide population over age 60 is predicted to reach 2.1 billion by 2050, more than a 20% increase over the current number. Such an expansion in this population over the next few decades will pose a greatly increased public health burden making development of elderly RSV vaccines an important priority. This project will develop novel virus-like particles (VLPs) as an RSV vaccine for elderly populations. These VLPs contain the RSV pre-fusion F protein and the G protein and are built on the core proteins of the avian Newcastle Disease Virus. They have been shown to be an effective vaccine in mice and cotton rats (CR). Importantly, they induce high titers of anti-RSV neutralizing antibody titers in animals previously infected with RSV (RSV primed), which mimics the adult human population. They are also effective as a maternal vaccine protecting offspring of immunized animals from RSV challenge. In this project, we hypothesize that using an immunologically superior form of VLP associated pre-F RSV protein in a reproducible and representative human model of RSV infections, we will be able to produce enhanced protective RSV immune responses in the elderly that will surpass those of standard pre-F RSV protein vaccines. Using RSV experienced, elderly cotton rats as human surrogates, we propose three specific aims to develop these VLPs as an RSV vaccine for elderly populations. Aim 1: to ascertain if pre-fusion F VLP immunization of elderly CRs will recall RSV memory induced in young CRs. Aim 2: to determine if pre-fusion F VLP immunization of RSV primed, young CRs can result in protective antibodies in elderly CR with or without a second VLP boost immunization. Aim 3: to assess if VLP induced protective responses in elderly CRs can be further augmented by adjusted doses of VLPs, route of immunization, or addition of adjuvants.